Health-related quality of life of perinatally HIV-infected young people: a longitudinal study.

Young people perinatally infected with HIV (pHIV) are at risk of a lowered health-related quality of life (HRQOL). Previous evaluation of the NeurOlogical, VIsual and Cognitive performance in HIV-infected Children (NOVICE)-cohort showed no difference in HRQOL between pHIV and matched HIV-uninfected controls (HIV-), yet a higher percentage of pHIV had impaired HRQOL. The aim of this study is to compare the change over time in HRQOL of pHIV to HIV- over a 5-year period. We used the Pediatric Quality of Life Inventory (PedsQL)™ 4.0 to repeat HRQOL assessment. High PedsQL scores indicate good HRQOL. Fifteen/33 (45.5%) pHIV and 17/37 (45.9%) HIV- completed both assessments. At the first assessment, the mean age was 13.1 years (range 8.0-18.4). PHIV scored higher than HIV- on Emotional functioning and on Total scale score. After five years, the mean age was 17.6 years (range 12.1-22.8). PHIV scored higher than HIV- on all scales, except Social functioning. PHIV did not differ significantly from the Dutch norm on either time-point. LMEM showed no difference in change over time for any of the PedsQL scales. In this study, young people with pHIV receiving high-quality health care, including monitoring of HRQOL, remain to experience a good HRQOL.

Paediatric European Network for Treatment of AIDS (PENTA) guidelines for treatment of paediatric HIV-1 infection 2015: optimizing health in preparation for adult life.

The 2015 Paediatric European Network for Treatment of AIDS (PENTA) guidelines provide practical recommendations on the management of HIV-1 infection in children in Europe and are an update to those published in 2009. Aims of treatment have progressed significantly over the last decade, moving far beyond limitation of short-term morbidity and mortality to optimizing health status for adult life and minimizing the impact of chronic HIV infection on immune system development and health in general. Additionally, there is a greater need for increased awareness and minimization of long-term drug toxicity. The main updates to the previous guidelines include: an increase in the number of indications for antiretroviral therapy (ART) at all ages (higher CD4 thresholds for consideration of ART initiation and additional clinical indications), revised guidance on first- and second-line ART recommendations, including more recently available drug classes, expanded guidance on management of coinfections (including tuberculosis, hepatitis B and hepatitis C) and additional emphasis on the needs of adolescents as they approach transition to adult services. There is a new section on the current ART 'pipeline' of drug development, a comprehensive summary table of currently recommended ART with dosing recommendations. Differences between PENTA and current US and World Health Organization guidelines are highlighted and explained.

Virological and Social Outcomes of HIV-Infected Adolescents and Young Adults in The Netherlands Before and After Transition to Adult Care.

BACKGROUND: As a result of effective combination antiretroviral therapy (cART) and advanced supportive healthcare, a growing number of human immunodeficiency virus (HIV)-infected children survive into adulthood. The period of transition to adult care is often associated with impaired adherence to treatment and discontinuity of care. We aimed to evaluate virological and social outcomes of HIV-infected adolescents and young adults (AYAs) before and after transition, and explore which factors are associated with virological failure. METHODS: We included 59 HIV-infected AYAs from the Netherlands who had entered into pediatric care and transitioned from pediatric to adult healthcare. We used HIV RNA load and cART data from the Dutch Stichting HIV Monitoring database (1996-2014), and collected social and treatment data from patients' medical records from all Dutch pediatric HIV treatment centers and 14 Dutch adult treatment centers involved. We evaluated risk factors for virological failure (VF) in a logistic regression model adjusted for repeated measurements. RESULTS: HIV VF occurred frequently during the study period (14%-36%). During the transition period (from 18 to 19 years of age) there was a significant increase in VF compared with the reference group of children aged 12-13 years (odds ratio, 4.26 [95% confidence interval, 1.12-16.28]; P = .03). Characteristics significantly associated with VF were low educational attainment and lack of autonomy regarding medication adherence at transition. CONCLUSIONS: HIV-infected AYAs are vulnerable to VF, especially during the transition period. Identification of HIV-infected adolescents at high risk for VF might help to improve treatment success in this group.

Tuberculids: cutaneous indicator diseases of Mycobacterium tuberculosis infection in young patients.

BACKGROUND: In the past years the incidence of tuberculosis has dropped significantly in most parts of Europe and the presentation of symptomatic tuberculosis cases have become increasingly rare. With the recent influx of refugees in Europe coming from tuberculosis endemic areas like the Middle East and Africa, it is expected that the incidence of tuberculosis will increase. OBJECTIVES: Cutaneous symptoms are important hallmarks that can be of aid for the correct diagnosis of an underlying disease, like tuberculosis. METHODS: We describe 2 young patients with tuberculids, respectively lichen scrofulosorum and papulonecrotic tuberculids, caused by a systemic Mycobacterium tuberculosis infection. RESULTS: Tuberculids are cutaneous immunological reactions triggered by a Mycobacterium tuberculosis infection elsewhere in the body. The three main manifestations of cutaneous tuberculids are: lichen scrofulosorum, papulonecrotic tuberculids and erythema induratum of Bazin. Whereas the latter is more common, the first two presentations are rare. CONCLUSION: It is of importance that clinicians, including dermatologists, are aware of the spectrum of clinical presentations of tuberculosis to halt this destructive and highly contagious disease early in its course.

Lower IQ and poorer cognitive profiles in treated perinatally HIV-infected children is irrespective of having a background of international adoption.

BACKGROUND: HIV-associated cognitive deficiency in perinatally HIV-infected (PHIV) children has been studied in Western countries in a population of which an increasing proportion has been internationally adopted. Studies often lack an appropriate internationally adopted HIV-uninfected control group, potentially confounding the relationship between HIV and cognitive functioning. This study aims to further elucidate the association between treated HIV infection and cognitive development by addressing the background of international adoption. METHODS: We cross-sectionally studied the impact of HIV on cognition by comparing PHIV children and HIV- uninfected controls, matched for age-, sex-, ethnicity-, socioeconomic status (SES)- and adoption status. We used a standardized neuropsychological test battery to measure intelligence (IQ), and the cognitive domains of processing speed, working memory, executive function, learning ability and visual-motor function and compared outcomes using lineair regression models, adjusted for IQ. We determined cognitive profiles and cognitive impairment by using multivariate normative comparison (MNC) and explored associations with HIV disease- and treatment-related factors. RESULTS: We enrolled fourteen PHIV children (mean age 10.45 years [1.73 SD], 93% adopted from sub-Saharan Africa at a median age of 3.3 years [IQR 2.1-4.2]) and fifteen HIV- uninfected controls. Groups did not clinically nor statistically differ in age, sex, ethnicity, SES, region of birth, adoption status and age at adoption. PHIV scored consistently lower on all cognitive domains and MNC outcomes. Compared to controls, PHIV children had a significant lower IQ (mean 81 [SD 11] versus mean 97 [SD 15], p = 0.005), and a poorer cognitive profile by MNC (Hotelling's T2 mean -4.36 [SD 5.6] versus mean 0.16 [SD 4.5], p = 0.021), not associated with HIV disease- and treatment-related factors. Two PHIV (14%) and one control (7%) were classified as cognitively impaired (p = 0.598). CONCLUSIONS: Findings indicate treated HIV-infection to be independently associated with lower IQ and poorer cognitive profiles in PHIV children, irrespective of a background of international adoption.

Systemic and intrathecal immune activation in association with cerebral and cognitive outcomes in paediatric HIV.

Despite treatment, immune activation is thought to contribute to cerebral injury in children perinatally infected with human immunodeficiency virus (HIV). We aimed to characterize immune activation in relation to neuroimaging and cognitive outcomes. We therefore measured immunological, coagulation, and neuronal biomarkers in plasma and cerebrospinal fluid (CSF) samples of 34 perinatally HIV-infected children aged 8-18 years, and in plasma samples of 37 controls of comparable age, sex, ethnicity, and socio-economic status. We then compared plasma biomarker levels between groups, and explored associations between plasma/CSF biomarkers and neuroimaging and cognitive outcomes using network analysis. HIV-infected children showed higher plasma levels of C-reactive protein, interferon-gamma, interferon-gamma-inducible protein-10, and monocyte chemoattractant protein-1 than controls. In HIV-infected participants, plasma soluble CD14 was positively associated with microstructural white matter (WM) damage, and plasma D-dimer was negatively associated with WM blood flow. In CSF, IL-6 was negatively associated with WM volume, and neurofilament heavy-chain (NFH) was negatively associated with intelligence quotient and working memory. These markers of ongoing inflammation, immune activation, coagulation, and neuronal damage could be used to further evaluate the pathophysiology and clinical course of cerebral and cognitive deficits in perinatally acquired HIV.

Macrophage-tropic variants initiate human immunodeficiency virus type 1 infection after sexual, parenteral, and vertical transmission.

Macrophage-tropic, non-syncytium-inducing, HIV-1 variants predominate in the asymptomatic phase of infection and may be responsible for establishing infection in an individual exposed to the mixture of HIV-1 variants. Here, genotypical and phenotypical characteristics of virus populations, present in sexual, parenteral, or vertical donor-recipient pairs, were studied. Sequence analysis of the V3 domain confirmed the presence of a homogeneous virus population in recently infected individuals. Biological HIV-1 clones were further characterized for syncytium inducing capacity on the MT2 cell line and for macrophage tropism as defined by the appearance of proviral DNA upon inoculation of monocyte-derived macrophages. Both sexual and parenteral transmission cases revealed a selective outgrowth in the recipient of the most macrophage-tropic variant(s) present in the donor. In three out of five vertical transmission cases, more than one highly macrophage-tropic virus variant was present in the child shortly after birth, suggestive of transmission of multiple variants. In three primary infection cases, homogeneous virus populations of macrophage-tropic, non-syncytium-inducing variants were present prior to seroconversion, thus excluding humoral immunity as the selective pressure in favour of macrophage-tropic variants. These observations may have important implications for vaccine development.

Early recovery of CD4+ T lymphocytes in children on highly active antiretroviral therapy. Dutch study group for children with HIV infections.

INTRODUCTION: Regeneration of CD4+ T lymphocytes has been shown to be thymus-dependent in bone marrow transplant recipients and after intensive chemotherapy. The rate of CD4+ T cell regeneration is correlated positively with enlargement of the thymus, as shown on radiographs, and higher rates of CD4+ T lymphocyte regeneration were observed in children as compared with adults, consistent with thymic function diminishing with age. We hypothesized that in HIV infected patients CD4+ T cell recovery during highly active antiretroviral therapy (HAART) may also be thymus dependent. Therefore, repopulation of naive (CD45RA+), memory (CD45RO+) and total CD4+ T lymphocytes and total CD8+ T lymphocytes in peripheral blood was assessed in 13 HIV infected children during the initial 3 months of HAART. RESULTS: Significantly higher recovery rates of naive, memory and total CD4+ T cells were observed in children below the age of 3 years as compared with older children. Kinetics of total CD8+ T cells showed no relation to age. Moreover, recovery rates of naive CD4+ T cells in patients below 3 years of age were 10-40 fold higher as compared with previously reported naive CD4+ T cell recovery rates in adults on HAART. CONCLUSIONS: High recovery rates of naive, memory and total CD4+ T cells can be achieved in children below 3 years of age. Changes in CD8 counts did not correlate with age. These results indicate that regeneration of CD4+ T cells during HAART may be a thymus-dependent process.

Therapeutic immune reconstitution in HIV-1-infected children is independent of their age and pretreatment immune status.

OBJECTIVE: To evaluate long-term immune reconstitution of children treated with highly active antiretroviral therapy (HAART). METHODS: The long-term immunological response to HAART was studied in 71 HIV-1-infected children (aged 1 month to 18 years) in two prospective, open, uncontrolled national multicentre studies. Blood samples were taken before and after HAART was initiated, with a follow-up of 96 weeks, and peripheral CD4 and CD8 T cells plus naive and memory subsets were identified in whole blood samples. Relative cell counts were calculated in relation to the median of the age-specific reference. RESULTS: The absolute CD4 cell count and percentage and the CD4 cell count as a percentage of normal increased significantly (P < 0.001) to medians of 939 x 106 cells/l (range, 10-3520), 32% (range, 1-50) and 84% (range, 1-161), respectively, after 48 weeks. This increase was predominantly owing to naive CD4 T cells. There was a correlation between the increase of absolute naive CD4 T cell counts and age. However, when CD4 T cell restoration was studied as percentage of normal values, the inverse correlation between the increase of naive CD4 T cell count and age was not observed. In addition, no difference in immunological reconstitution was observed at any time point between virological responders and non-responders. CONCLUSIONS: Normalization of the CD4 cell counts in children treated with HAART is independent of age, indicating that children of all age groups can meet their CD4 T cell production demands. In general, it appears that children restore their CD4 T cell counts better and more rapidly than adults, even in a late stage of HIV-1 infection.

Factors influencing the relapse risk at steroid dose reduction in myasthenia gravis.

In a selected group of 69 patients with myasthenia gravis treated with prednisone, the factors were studied that might have influenced the reoccurrence or exacerbation of clinical signs after initial improvement in two-thirds of the patients. It was not evident that the speed of dose reduction was responsible for the relapse in most patients. Azathioprine added to the prednisone regimen was found to reduce the relapse rate at steroid reduction. Pure ocular cases and patients who underwent thymectomy without thymoma had a higher chance to remain in remission after prednisone was stopped. Maintenance dose could be determined in 18 patients and was 0.42 mg/kg/2 d., but the difference between patients with or without azathioprine was not significant.

[HIV infection in pregnant women in The Netherlands]. / HIV-infectie bij zwangere vrouwen in Nederland.

A review is given of the pregnant women with HIV infection known to the co-ordinating centre of the 'Dutch prospective study of HIV seropositive pregnant women and their children'. Fifty-five women with 57 pregnancies were discovered between 1 September 1985 and 1 January 1991. Of these women, 60% were not of Dutch origin and 56% were living in Amsterdam. Thirty-two women were (former) intravenous drug users. In 23 women heterosexual transmission was likely; two women were also blood transfusion recipients. Nearly half (11/23) of these women came from, or had a partner from, an AIDS-endemic area. In 16 women HIV seropositivity was known before pregnancy. Twenty-four women were specifically tested during pregnancy or within 1 week after parturition because of risk factors for HIV infection. Fifteen women were discovered in a HIV screening programme of pregnant women in Amsterdam (n = 13) and the University Hospital of Groningen (n = 2). At first, eight of these women did not mention risk factors. Thirty-five women could choose abortion (less than or equal to 20 weeks of gestation); the majority (69%) decided to continue pregnancy. Twelve pregnancies ended in an elective or spontaneous abortion, 39 in the birth of 40 children (one pair of twins) of whom 39 were viable, three women were still pregnant and of three the pregnancy outcome was unknown. Preterm delivery (8/39) and birth weight less than 2500 gram (7/39) were seen frequently, the latter particularly in women (formerly) using intravenous drugs (6/25).

[The treatment of 12 HIV-infected children with zidovudine]. / Behandeling van 12 met HIV geïnfecteerde kinderen met zidovudine.

12 HIV-infected children were treated with a high dose of zidovudine (800/mg/m2/day) during a mean follow up period of 18 months. After starting treatment with zidovudine there was a subjective improvement and an increase in body weight, and a significant decline in serum HIV-antigenemia (p < 0.01) and serum IgG levels (p < 0.05). Zidovudine was generally well tolerated but there was serious hematological toxicity. In 9 patients (75%) dose reduction was necessary because of severe anemia (3 patients) or leucopenia (6 patients). Because of the high incidence of these side effects the starting dose of zidovudine was reduced to 600 mg/m2/day. These results confirm that zidovudine can safely be used to treat HIV-infected children. The main limitation is serious hematological toxicity which appears to be dose-related.

[Treatment of HIV-1 infected pregnant women]. / De behandeling van HIV-1-geïnfecteerde zwangeren.

Since 1 January 2004, pregnant women in the Netherlands have been universally screened for HIV infection. Three HIV-infected, pregnant women aged 28, 24 and 33 years respectively, illustrate some of the problems that may be encountered in this situation, as well as the treatment options available to prevent the transmission of HIV from mother to child. The first patient had a positive antibody test early in pregnancy for which she did not need treatment, the second had a positive antibody test late in pregnancy and the third was seropositive and on medication, but had the wish to become pregnant. A vaginal delivery is possible when highly active antiretroviral therapy (HAART) of the mother is started in good time and the plasma HIV-RNA is < 400 copies/ml at the time of delivery. In this situation the risk of transmission is reduced to around 1%. However, if HIV infection is diagnosed late in pregnancy or, despite HAART, the plasma HIV-RNA is not expected to be < 400 copies/ml, an elective caesarean section is scheduled at 38 weeks of pregnancy. In all instances the neonate is treated for 28 days with antiretrovirals, as post-exposure prophylaxis. If a woman with a known HIV infection wants to become pregnant, the choice of antiretroviral regimen and when this is started is determined by her treatment history and the potential toxic effects of the medication on the foetus.

[Reduction of vertical transmission by means of perinatal prophylaxis in the case of children exposed to HIV-1 and born in the Netherlands during the period 1995-1999]. / Reductie van verticale transmissie door perinatale profylaxe bij aan HIV-1 geëxposeerde in Nederland geboren kinderen in de periode 1995-1999.

OBJECTIVE: Registration of the number of children born to HIV-infected mothers diagnosed prepartum and analysis of the efficacy of the policy for preventing mother-to-child transmission of HIV-1 in the period 1995 to 1999. DESIGN: Prospective. METHOD: On a monthly basis, Dutch paediatricians reported HIV-1 exposed children to the Dutch Paediatric Surveillance Unit. All reports were followed up with standard questionnaires. An additional retrospective study was performed because of incomplete registration. Paediatricians in centres for the care of HIV-infected patients were requested to retrospectively report HIV-exposed children. The standard questionnaires were submitted to these paediatricians. Data were collected during the period 1 January 1995-31 December 1999. RESULTS: The number of children known to be exposed to HIV-1 and for whom the mother was diagnosed prepartum, increased from 5 to 25 per year. The percentage of HIV-1 infected children decreased from 20% (1/5) to 4% (1/25). The number of pregnant HIV-1 infected women using highly active antiretroviral therapy increased during the study period from 0% (0/5) to 72% (18/25). Antiretroviral therapy was administered to 92% (23/25) of HIV-1 exposed children. In total 2% of the children received breastfeeding. CONCLUSION: Despite an increase in the number of children known to be exposed to HIV-1, a decrease in the percentage of HIV-1-infected children was observed. Of the children born in 1999 and known to be exposed to HIV-1, 4% were infected. Measures taken in the Netherlands to prevent mother-to-child transmission of HIV-1 infection are effective.

[HIV infections in childhood]. / Infecties met HIV op de kinderleeftijd.

After the presentation of 3 case histories of children who became infected with HIV through different modes of transmission the disease is further discussed. Special attention is paid on epidemiology, transmission pathways, pathophysiology, making the diagnosis, clinical symptoms, therapy and prognosis of HIV infected children.

Paediatric European Network for Treatment of AIDS (PENTA) guidelines for treatment of paediatric HIV-1 infection 2015: optimizing health in preparation for adult life

The 2015 Paediatric European Network for Treatment of AIDS (PENTA) guidelines provide practical recommendations on the management of HIV-1 infection in children in Europe and are an update to those published in 2009. Aims of treatment have progressed significantly over the last decade, moving far beyond limitation of short-term morbidity and mortality to optimizing health status for adult life and minimizing the impact of chronic HIV infection on immune system development and health in general. Additionally, there is a greater need for increased awareness and minimization of long-term drug toxicity. The main updates to the previous guidelines include: an increase in the number of indications for antiretroviral therapy (ART) at all ages (higher CD4 thresholds for consideration of ART initiation and additional clinical indications), revised guidance on first- and second-line ART recommendations, including more recently available drug classes, expanded guidance on management of coinfections (including tuberculosis, hepatitis B and hepatitis C) and additional emphasis on the needs of adolescents as they approach transition to adult services. There is a new section on the current ART 'pipeline' of drug development, a comprehensive summary table of currently recommended ART with dosing recommendations. Differences between PENTA and current US and World Health Organization guidelines are highlighted and explained